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ID PMID Title PublicationDate abstract
9743215 Synovial fluid cytokines in patients with rheumatoid arthritis or other arthritic lesions. 1998 Sep The synovial fluid (SF) of rheumatoid arthritis (RA) patients contains a mixture of inflammatory mediators. In order to determine whether certain cytokine patterns locally in the joint are specifically related to the chronic inflammation in RA, the concentrations of interleukin (IL)-1alpha, IL-1beta, IL-6, IL-10, transforming growth factor-beta (TGF-beta), tumour necrosis factor-alpha (TNF-alpha) and IgG2b-inducing factor (IgG2bIF) were measured in SF from 22 patients with RA and 22 patients with other types of arthritic lesions. High levels of IL-10, latent and active TGF-beta and the presence of IgG2bIF are significantly correlated with RA when corrected for age. As these factors have the capacity to promote antibody production, they might contribute to the maintenance of local antibody production in RA synovial tissues. All RA-SF samples contained detectable levels of IL-10 and all except one contained IL-1beta, while concentrations in several non-RA-SF samples were below detection limits. IL-6 and TGF-beta were present in all SF samples from both RA and non-RA patients. The presence of IgG2bIF was strongly correlated with high levels of IL-10 and IL-1beta in SF. However, no distinct cytokine profile specific for the chronic inflammation characteristic of RA was found.
11336920 Altered mRNA level of matrix metalloproteinase-13 in MH7A synovial cells under mechanical 2001 Apr In an effort to elucidate the interplay between mechanical load and proteolytic gene expression in arthritic tissue degradation, we investigated cellular morphology and mRNA levels of matrix metalloproteinase-13 (MMP-13) genes under mechanical stress in human MH7A synovial cells. The cells were isolated from the knee joint of a rheumatoid arthritis patient. Using a reverse transcription-polymerase chain reaction procedure, we found that loading by an oscillatory shaker transiently decreased the level of MMP-13 mRNA and unloading by a clinostat increased its mRNA level. The unloaded cells appeared to be rounded and displayed a poorly developed track of peripheral fibers, whereas the cells under loading tended to align to the shear flow and were elongated. We also found that altering the oscillatory direction of mechanical loads contributed to a further reduction in mRNA expression of MMP-13. Our results demonstrate the role of mechanical loading and unloading in the transcriptional regulation of MMP-13 in synovial cells, and suggest the potential value of physical therapy for arthritic joints.
9477771 Photodynamic synovectomy using benzoporphyrin derivative in an antigen-induced arthritis m 1998 Jan Experimental photodynamic therapy (PDT) has recently been adapted for the treatment of inflammatory and rheumatoid arthritis. The biodistribution of benzoporphyrin derivative monoacid ring A (BPD-MA) and the effect of percutaneous light activation via intra-articular bare cleaved optical fibers was investigated using a rabbit-antigen-induced arthritis model. Qualitative evaluation of intra-articular photosensitizer clearance was performed with laser-induced fluorescence from 0 to 6 h following intravenous injection. The compound was rapidly taken up within the joint and then cleared steadily over the 6 h interval. Biodistribution was determined by fluorescence microscopy and spectrofluoroscopic extraction techniques 3 h following intravenous injection of 2 mg/kg BPD-MA. The biodistribution study demonstrated elevated levels of BPD-MA in synovium (0.35 microgram/g) and muscle (0.35 microgram/g). Fluorescence microscopy demonstrated presence of the compound within pathologic synovium but absence of the photosensitizer within meniscus, ligament, bone and articular cartilage. Tissue effects were evaluated histologically at 2 and 4 weeks posttreatment. BPD-MA-mediated PDT caused synovial necrosis in the region of light activation in 50% of treatment knees at 2 weeks and 43% at 4 weeks. No damage to nonpathologic tissues was observed. These studies indicate that selective destruction of synovium can be achieved by the light-activated photosensitizing agent BPD-MA without damage to articular cartilage or periarticular soft tissues. PDT needs to be further evaluated to optimize treatment parameters to provide for a new minimally invasive synovectomy technique.
9209836 Use of colony-stimulating factors in the treatment of neutropenia associated with collagen 1997 May Chronic neutropenia associated with collagen vascular disease is seen principally with Felty's syndrome complicating rheumatoid arthritis. Multiple recent reports document the efficacy of both granulocyte-macrophage colony-stimulating factor (GM-CSF) and granulocyte colony-stimulating factor (G-CSF) in reversing the neutropenia and decreasing the risk of infections in Felty's syndrome. Long-term use of G-CSF appears well tolerated and effective in Felty's syndrome. Of concern, however, have been flares of arthritis and development of leukocytoclastic vasculitis in several patients following the use of colony-stimulating factors (CSFs) in Felty's syndrome. The incidence of these complications of CSF therapy appears to be greater in Felty's syndrome than in other disorders. Future studies will need to address the incidence of these side effects, evaluate strategies to reduce risks, and clarify the optimum use of CFSs in Felty's syndrome.
10025915 Establishment and characterization of nurse cell-like stromal cell lines from synovial tis 1999 Feb OBJECTIVE: To investigate the features of synovial stromal cells established from patients with rheumatoid arthritis (RA), and to define these cells as nurse cells. METHODS: Synovial nurse-like stromal cell lines (RA-SNCs) were established from patients with RA. These cell lines were examined for morphology, pseudoemperipolesis activity, cell surface markers, and cytokine production. The interaction between these RA-SNCs and a synovial tissue B cell clone was also examined. RESULTS: RA-SNCs had nurse cell activity. They spontaneously produced interleukin-6 (IL-6), IL-8, granulocyte colony-stimulating factor, and granulocyte-macrophage colony-stimulating factor. Furthermore, they produced IL-1beta and tumor necrosis factor alpha and expressed higher levels of the other cytokines after coculture with the B cell clone. Proliferation and Ig production by the B cell clone were dependent on direct contact with RA-SNCs. CONCLUSION: These results indicate that the RA-SNCs were nurse cells. The findings suggest that RA-SNCs may play an important role in the pathogenesis of RA by producing large amounts of cytokines and maintaining infiltrating lymphocytes.
11724514 Current topics on cytapheresis technologies. 2001 Aug Cytapheresis has been investigated recently for the treatment of autoimmune related diseases, such as rheumatoid arthritis (RA), inflammatory bowel disease (IBD), multiple sclerosis, and so on. A large number of physicians have indicated that patients with autoimmune diseases respond to cytapheresis treatment. The effective mechanism of cytapheresis for immune disorders is still controversial. However, the removal of the leukocyte including granulocyte, lymphocyte, and monocyte may play a crucial role in correcting imbalance of the immune system. A session of cytapheresis including leukocytapheresis (LCAP) and granulocytapheresis (GCAP) may not create a sufficient amount of cell removal for the human body. However, the cell removal can be a trigger of the immunomodulation as the treatment for immune disorder. Furthermore, not only cell removal but also reaction by blood contacting with medical device materials may play a role as an immunomodulation for immune disorders. This review introduces current cytapheresis technologies and attempts to elucidate the effective mechanism of cytapheresis for immune disorders, focused on LCAP and/or GCAP for RA or IBD.
9294578 Rheumatoid nodules: MR/pathological correlation. 1997 Sep PURPOSE: To demonstrate the signal characteristics of subcutaneous rheumatoid nodules in correlation to their histopathologic features. METHOD: The magnetic resonance imaging (MRI) features of biopsy proven subcutaneous rheumatoid nodules are described in five patients with rheumatoid arthritis established by classic criteria. RESULTS: Two morphologic appearances of rheumatoid nodules were observed on MRI: one predominantly cystic, with enhancing peripheral component; and a second type which is predominantly solid, with uniform enhancement following gadolinium injection. CONCLUSION: Subcutaneous rheumatoid nodules can appear by MR as solid, cystic, or a combination of both components. This closely correlates with their histopathologic evolution.
9751087 Therapeutic efficacy of multiple intravenous infusions of anti-tumor necrosis factor alpha 1998 Sep OBJECTIVE: To evaluate the efficacy, pharmacokinetics, immunogenicity, and safety of multiple infusions of a chimeric monoclonal anti-tumor necrosis factor alpha antibody (cA2) (infliximab; Remicade, Centocor, Malvern, PA) given alone or in combination with low-dose methotrexate (MTX) in rheumatoid arthritis (RA) patients. METHODS: In a 26-week, double-blind, placebo-controlled, multicenter trial, 101 patients with active RA exhibiting an incomplete response or flare of disease activity while receiving low-dose MTX were randomized to 1 of 7 groups of 14-15 patients each. The patients received either intravenous cA2 at 1, 3, or 10 mg/kg, with or without MTX 7.5 mg/week, or intravenous placebo plus MTX 7.5 mg/week at weeks 0, 2, 6, 10, and 14 and were followed up through week 26. RESULTS: Approximately 60% of patients receiving cA2 at 3 or 10 mg/kg with or without MTX achieved the 20% Paulus criteria for response to treatment, for a median duration of 10.4 to >18.1 weeks (P < 0.001 versus placebo). Patients receiving cA2 at 1 mg/kg without MTX became unresponsive to repeated infusions of cA2 (median duration 2.6 weeks; P=0.126 versus placebo). However, coadministration of cA2 at 1 mg/kg with MTX appeared to be synergistic, prolonging the duration of the 20% response in >60% of patients to a median of 16.5 weeks (P < 0.001 versus placebo; P=0.006 versus no MTX) and the 50% response to 12.2 weeks (P < 0.001 versus placebo; P=0.002 versus no MTX). Patients receiving placebo infusions plus suboptimal low-dose MTX continued to have active disease, with a Paulus response lasting a median of 0 weeks. A 70-90% reduction in the swollen joint count, tender joint count, and C-reactive protein level was maintained for the entire 26 weeks in patients receiving 10 mg/kg of cA2 with MTX. In general, treatment was well tolerated and stable blood levels of cA2 were achieved in all groups, except for the group receiving 1 mg/kg of cA2 alone, at which dosage antibodies to cA2 were observed in approximately 50% of the patients. CONCLUSION: Multiple infusions of cA2 were effective and well tolerated, with the best results occurring at 3 and 10 mg/kg either alone or in combination with MTX in approximately 60% of patients with active RA despite therapy with low-dose MTX. When cA2 at 1 mg/kg was given with low-dose MTX, synergy was observed. The results of the trial provide a strategy for further evaluation of the efficacy and safety of longer-term treatment with cA2.
10908686 Magnetic resonance imaging in early inflammatory arthritis: what is its role? 2000 Jul Magnetic resonance imaging (MRI) has important applications in musculoskeletal medicine. It allows the visualization of bone and soft tissues in three dimensions using a multiplanar technique and is uniquely suited to imaging the rheumatoid joint. Bony erosions are seen well using MRI in early rheumatoid arthritis and are frequently detected before they appear on plain radiographs. Bone marrow oedema is another important MRI feature associated with inflammatory joint disease and may be a forerunner of erosion. Synovial membrane inflammation and hypertrophy are detected after contrast enhancement and also by the use of dynamic MRI techniques, which provide a non-invasive method to accurately measure the inflammatory process. This information can be analysed and collated using MRI scoring systems and ultimately may be used to improve diagnostic accuracy, predict prognosis and monitor therapy in these patients. This review examines the case for the use of MRI in early inflammatory arthritis, outlining its strengths and potential weaknesses as an imaging modality in this context and indicating its potential role in clinical practice.
10796462 Low level laser therapy (classes I, II and III) in the treatment of rheumatoid arthritis. 2000 BACKGROUND: Rheumatoid arthritis (RA) affects a large proportion of the population. Low Level Laser Therapy (LLLT) was introduced as an alternative non-invasive treatment for RA about 10 years ago. LLLT is a light source that generates extremely pure light, of a single wavelength. The effect is not thermal, but rather related to photochemical reactions in the cells. The effectiveness of LLLT for rheumatoid arthritis is still controversial. OBJECTIVES: To assess the effectiveness of LLLT in the treatment of RA. SEARCH STRATEGY: We searched MEDLINE, EMBASE, the registries of the Cochrane Musculoskeletal group and the field of Rehabilitation and Related Therapies as well as the Cochrane Controlled Trials Register up to January 30, 2000. SELECTION CRITERIA: Following an a priori protocol, we selected only randomized controlled trials of LLLT for the treatment of patients with a clinical diagnosis of RA were eligible. Abstracts were excluded unless further data could be obtained from the authors. DATA COLLECTION AND ANALYSIS: Two reviewers independently select trials for inclusion, then extracted data and assessed quality using predetermined forms. Heterogeneity was tested with Cochran's Q test. A fixed effects model was used throughout for continuous variables, except where heterogeneity existed, in which case, a random effects model was used. Results were analyzed as weighted mean differences (WMD) with 95% confidence intervals (CI), where the difference between the treated and control groups was weighted by the inverse of the variance. Standardized mean differences (SMD) were calculated by dividing the difference between treated and control by the baseline variance. SMD were used when different scales were used to measure the same concept (e.g. pain). Dichotomous outcomes were analyzed with odds ratios. MAIN RESULTS: A total of 204 patients were included in the five placebo-controlled trials, with 112 randomized to laser therapy. Relative to a separate control group, LLLT reduced pain by 70% relative to placebo and reduced morning stiffness duration by 27.5 minutes (95%CI: 2.9 to 52 minutes) and increased tip to palm flexibility by 1.3 cm (95% CI: 0. 8 to 1.7 cm). Other outcomes such as functional assessment, range of motion and local swelling did not differ between groups. There were no significant differences between subgroups based on LLLT dosage, wavelength, site of application or treatment length. For RA, relative to a control group using the opposite hand, there was no difference between the control and treatment hand, but all hands improved in terms of pain relief and disease activity. REVIEWER'S CONCLUSIONS: In summary, LLLT for RA is beneficial as a minimum of a four-week treatment with reductions in pain and morning stiffness. On the one hand, this meta-analysis found that pooled data gave some evidence of a clinical effect, but the outcomes were in conflict, and it must therefore be concluded that firm documentation of the application of LLLT in RA is not possible. Clinicians and researchers should consistently report the characteristics of the LLLT device and the application techniques used. New trials on LLLT should make use of standardized, validated outcomes. Despite some positive findings, this meta-analysis lacked data on how LLLT effectiveness is affected by four important factors: wavelength, treatment duration of LLLT, dosage and site of application over nerves instead of joints.
9002037 Genetic mapping of susceptibility loci in the genes involved in rheumatoid arthritis. 1997 Jan Eighty-nine multicase rheumatoid arthritis families, each containing at least one affected sib pair, have been studied for evidence of genetic linkage to a panel of 315 microsatellite DNA markers. The families were located through the UK national data repository of the Arthritis and Rheumatism Council. Microsatellites were genotyped by semiautomated technology using Applied Biosystems sequencers (ABI 373). Using the SIBPAIR statistical package, linkage to HLA was confirmed (p < 0.0003). Several possible linkages outside HLA were noted, including at least one (p < 0.004) that merits further investigation.
11519772 Psychometric evaluation of the 12-item short-form health survey (SF-12) in osteoarthritis 2001 Jul BACKGROUND: The psychometric properties of the 12-Item Short-Form Health Survey (SF-12), a subset of the Medical Outcomes Study 36-Item Short-Form Health Survey (SF-36), have been tested in the general population and certain disease states. OBJECTIVE: The purpose of this study was to evaluate the psychometric properties of the SF-12 as a generic measure of health-related quality of life (HRQoL) in osteoarthritis (OA) and rheumatoid arthritis (RA) patient populations in clinical trials. METHODS: Data were aggregated from 5 clinical trials evaluating the efficacy of non-steroidal anti-inflammatory drugs in OA (n = 651) and RA (n = 693) patients. Patient assessments in these trials were made using the SF-36 and commonly used clinical measures of OA and RA at baseline and after up to 6 weeks of treatment. For the items of the SF-36 contained in the SF-12, the item missing rate, computability of scores, floor and ceiling effects, factor structure, and item-component correlations were evaluated. Clinical variables and correlations of physical component summary (PCS-12) and mental component summary (MCS-12) scores of the SF-12 with the corresponding SF-36 component summary scores (PCS-36 and MCS-36) were also examined. Analyses were conducted separately for OA and RA patients. RESULTS: A low individual SF-12 item missing rate (0.29% to 2.30%) and a high percentage score computability (90.9%-94.3%) were observed at baseline. No floor or ceiling effects at baseline were observed. The scree plot confirmed the 2-factor structure of the SF-12 items. Items belonging to the physical component correlated more strongly with the PCS-12 than with the MCS-12; similarly, items belonging to the mental component correlated more strongly with the MCS-12 than with the PCS-12. The correlations between the PCS-12 and PCS-36 and between the MCS-12 and MCS-36 ranged from 0.92 to 0.96 (P < 0.001) at baseline and at week 2, 4, or 6. Significant correlations ranging from -0.09 to -0.58 (P < 0.05) were observed between the SF-12 scores and clinical variables. CONCLUSION: The SF-12 appears to be a psychometrically sound tool for the assessment of HRQoL in OA and RA patients.
11252943 [Secondary Gougerot-Sjogren syndrome]. 2001 Jan 31 Secondary Sjögren's syndrome is due to another disease. When it develops in connective tissue diseases, their causative role is unchallenged. In AIDS or hepatitis C, exocrine involvement is virus related. Whether or not it qualifies for Sjögren's syndrome is debated. Amyloidosis and sarcoidosis do not produce direct, autoimmune lesions of the glands, hence their exocrine involvements are considered as differential diagnoses. The most common Sjögren's syndrome is found in rheumatoid arthritis. When it appears, the arthritis has been evolving for years, and has reached its typical, seropositive and erosive stage. Accordingly, dryness is not a major concern and should be sought for by proper questioning, specially on eye dryness. When a secondary Sjögren's syndrome is an early complication of rheumatoid arthritis, it could be confused with a primary syndrome with prominent joint involvement. In systemic lupus erythematosus, secondary Sjögren's syndrome develops rarely in the first years of evolution but later in life, when the patient becomes menopausal. In systemic sclerosis, especially in CREST, secondary syndrome can lead to the discovery of the unsuspected connective tissue disease thanks to mouth dryness. It can reveal primary biliary cirrhosis or auto-immune hepatitis. Often precede a true primary Sjögren dysfunctions of the thyroid.
9586243 Can the patient's memory of the timing of pain events replace chart notes? 1998 Mar The reliability of the patient's memory as to when pain remitted and relapsed was studied ten years after knee replacement. Pain was chosen because it is the most frequent spontaneous patient complaint, and the remission and relapse points in time are clinically important. The standard for the comparison was information extracted from the medical records. The patient's information on the time of remission of pain could not be trusted. For relapse there was a fair but insufficient association (Spearman's correlation coefficient + 0.51).
11418687 Gammalinolenic acid, an unsaturated fatty acid with anti-inflammatory properties, blocks a 2001 Jul 1 Administration of gammalinolenic acid (GLA), an unsaturated fatty acid, reduces joint inflammation in patients with rheumatoid arthritis. Addition of GLA in vitro suppresses release of IL-1beta from human monocytes stimulated with LPS. LPS-induced IL-1beta release is followed by IL-1-induced IL-1beta release, an amplification process termed autoinduction. We show here with peripheral blood monocytes from normal volunteers and from patients with rheumatoid arthritis by using IL-1R antagonist to block autoinduction and IL-1alpha stimulation to simulate autoinduction that approximately 40% of IL-1beta released from LPS-stimulated cells is attributable to autoinduction and that GLA reduces autoinduction of IL-1beta while leaving the initial IL-1beta response to LPS intact. Experiments with cells in which transcription and protein synthesis were blocked suggest that GLA induces a protein that reduces pro-IL-1beta mRNA stability. IL-1beta is important to host defense, but the amplification mechanism may be excessive in genetically predisposed patients. Thus, reduction of IL-1beta autoinduction may be protective in some patients with endotoxic shock and with diseases characterized by chronic inflammation.
9257834 A solution to the rheumatoid factor paradox: pathologic rheumatoid factors can be tolerize 1997 Aug 15 Rheumatoid factors (RF) associated with arthritic joint erosion are only seen transiently, if at all, in nondiseased individuals. Therefore, a tolerance mechanism must exist that prevents pathologic RF B cells from expressing Abs. Surprisingly, it has been shown that pathologic RF B cells are not tolerized by any previously established tolerance mechanism such as deletion, receptor editing, anergy, or prevention of memory establishment. How are pathologic RF cells tolerized? By simulating the RF response with a cellular automaton model immune system, we demonstrate that pathologic RFs can be tolerized by the novel mechanism of "competitive tolerance" with natural, nonpathologic RFs. We then demonstrate that competitive tolerance can be broken when a sequestered pool of expanding B cells are inappropriately subjected to chronic stimulation (as appears to occur in MRL/lpr mice and in patients with rheumatoid arthritis).
11826743 [National database documentation for collecting, controlling and quality assurance of new 2001 Dec The national database of the German Collaborative Arthritis Centres is well-established in German rheumatology as a tool for the observation and assessment of treatments. The usage and spread of new drugs and treatment principles is regularly observed. Discussion about practice variations in treatment contributes to the internal quality assessment in the participating arthritis centres.
9236673 Reduction of serum matrix metalloproteinase 1 and matrix metalloproteinase 3 in rheumatoid 1997 Jun Matrix metalloproteinase (MMP)-1 and MMP-3 levels were measured in serum samples from rheumatoid arthritis (RA) patients undergoing a double-blinded placebo-controlled trial with the chimaeric anti-tumour necrosis factor (TNF)-alpha antibody cA2. Both MMP-1 (P < 0.015), but to a larger extent MMP-3 (P < 0.001) levels were elevated in all RA patients prior to the commencement of the trial compared with normal control sera. Following cA2 therapy, MMP-1 and MMP-3 levels were assessed in the placebo, and 1 and 10 mg/kg cA2-treated groups at 7, 14, 21 and 28 days. In both the 1 and the 10 mg/kg cA2-treated groups, a significant decrease in serum MMP-3 levels at all time points was observed, reducing maximally to 41% of pre-infusion values at day 7. MMP-1 levels were also reduced, but less dramatically than MMP-3, to 85% of pre-infusion values after 14 days in the 10 mg/kg cA2 treated group. In a separate non-placebo-controlled study, we also evaluated the tissue inhibitor of metalloproteinase (TIMP)-1 levels in plasma following cA2 infusion. Pre-infusion TIMP-1 levels were above the normal control range, but were significantly reduced (P < 0.035) 14 days after infusion to 72% of pre-infusion values. This study confirms previous reports that MMP-3 levels are elevated and correlate with measures of inflammation in RA, and furthermore demonstrate that serum MMP-3 and MMP-1 levels are downmodulated following anti-TNF-alpha antibody therapy. Whilst serum MMP-3 levels correlated with C-reactive protein (CRP) both prior to and following anti-TNF-alpha antibody therapy, it remains to be demonstrated that serum MMP-3 and/or MMP-1 levels reflect the cartilage and bone resorptive processes which are evident in this disease.
9710888 Soluble tumor necrosis factor receptor (p75) fusion protein (ENBREL) as a therapy for rheu 1998 Aug Soluble tumor necrosis factor (TNF) receptor fusion protein (p75) (Enbrel) is a reversible inhibitor of the biologic effects of TNF. Enbrel has been shown in placebo-controlled trials to significantly improve the signs and symptoms of rheumatoid arthritis. Clinical trials are now in progress to assess the safety and efficacy of Enbrel in combination with methotrexate in refractory rheumatoid arthritis along with trials to compare Enbrel to methotrexate in patients with early rheumatoid arthritis.
10343521 Influence of sulphasalazine, methotrexate, and the combination of both on plasma homocyste 1999 Feb OBJECTIVE: To study the influence of sulphasalazine (SSZ), methotrexate (MTX), and the combination (COMBI) of both on plasma homocysteine and to study the relation between plasma homocysteine and their clinical effects. METHODS: 105 patients with early rheumatoid arthritis (RA) were randomised between SSZ (2-3 g/day), MTX (7.5-15 mg/week), and the COMBI (same dose range) and evaluated double blindly during 52 weeks. Plasma homocysteine, serum folate concentrations, and vitamin B12 were measured. The influence of the C677T mutation of the enzyme methyl-enetetrahydrofolatereductase (MTHFR) gene was analysed. RESULTS: A slight trend towards increased efficacy and an increased occurrence of minor gastrointestinal toxicity was present in the COMBI group, no differences existed clinically between SSZ and MTX. Only a slight and temporary increase in plasma homocysteine was found in the SSZ group, in contrast with the persistent rise in the MTX group and the even greater increase in the COMBI patients. Patients homozygous for the mutation in the MTHFR gene had significantly higher baseline homocysteine, heterozygous MTHFR genotype induced a significantly higher plasma homoeysteine at week 52 compared with no mutation. No correlation was found between clinical efficacy variables and homocysteine. Patients with gastrointestinal toxicity had a significantly greater increase in homocysteine. CONCLUSION: A persistent increase in plasma homocysteine concentrations was observed in patients treated with MTX alone and more pronounced in combination with SSZ, in contrast with SSZ alone. An increase in plasma homocysteine is related to the C677T mutation in MTHFR. A relation in the change in homocysteine concentrations with (gastrointestinal) toxicity was found, no relation with clinical efficacy existed.